Differentiation of beta-like cells from human induced pluripotent stem cell-derived pancreatic progenitor organoids

Pedraza‐Arevalo, Sergio; Cujba, Ana-Maria; Fallas, Mario Enrique Alvarez; Sancho, Rocı́o

doi:10.1016/j.xpro.2022.101656

Cited by 3 publications

(2 citation statements)

References 4 publications

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“…This diagram is adapted from ref. 57 Fig. 1a, d under Public License CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/legalcode ).…”

Section: Resultsmentioning

confidence: 99%

USP7 controls NGN3 stability and pancreatic endocrine lineage development

Manea¹,

Nelson²,

Garrone³

et al. 2023

Nat Commun

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Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.

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“…This diagram is adapted from ref. 57 Fig. 1a, d under Public License CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/legalcode ).…”

Section: Resultsmentioning

confidence: 99%

USP7 controls NGN3 stability and pancreatic endocrine lineage development

Manea¹,

Nelson²,

Garrone³

et al. 2023

Nat Commun

Self Cite

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“…[1,[5][6][7] These differentiation methods rely on the activa-tion and inhibition of developmental signaling pathways with soluble molecules, including growth factors and small molecules, to guide PSCs to differentiate into pancreatic β cells. [8][9][10][11][12][13] However, even for PSC lines obtained from a single donor, variations manifest as spatial and functional heterogeneity of PSCs that emerge within in vitroexpanded PSC populations cultured under seemingly identical culture conditions. [14,15] Furthermore, significant variations in the efficiency of differentiation have been observed among different PSC lines, with some lineages differentiating more easily into a particular cell type than others.…”

Section: Introductionmentioning

confidence: 99%

A simple tool for the synchronous differentiation of human induced pluripotent stem cells into pancreatic progenitors

Kim,

Thanuthanakhun,

Kino‐oka

2023

Biotechnology Journal

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Efficient differentiation of human induced pluripotent stem cells (hiPSCs) into functional pancreatic cells holds great promise for diabetes research and treatment. However, a robust culture strategy for producing pancreatic progenitors with high homogeneity is lacking. Here, we established a simple differentiation strategy for generating synchronous iPSC‐derived pancreatic progenitors via a two‐step method of sequential cell synchronization using botulinum hemagglutinin (HA), an E‐cadherin function‐blocking agent. Of the various methods tested, the first‐step synchronization method with HA exposure induces a synchronous switch from E‐ to N‐cadherin and N‐ to E‐cadherin expression by spatially controlling heterogeneous cell distribution, subsequently improving their competency for directed differentiation into definitive endodermal cells from iPSCs. The iPSC‐derived definitive endodermal cells can efficiently generate PDX1+ and NKX6.1+ pancreatic progenitor cells in high yields. The PDX1+ and PDX1+/NKX6.1+ cell densities showed 1.6‐ and 2.2‐fold increases, respectively, compared with those from unsynchronized cultures. The intra‐run and inter‐run coefficient of variation were below 10%, indicating stable and robust differentiation across different cultures and runs. Our approach is a simple and efficient strategy to produce large quantities of differentiated cells with the highest homogeneity during multistage pancreatic progenitor differentiation, providing a potential tool for guided differentiation of iPSCs to functional insulin‐producing cells.

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Potential Use of Organoids in Regenerative Medicine

Septiana,

Pawitan

2024

Tissue Eng Regen Med

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Differentiation of beta-like cells from human induced pluripotent stem cell-derived pancreatic progenitor organoids

Cited by 3 publications

References 4 publications

USP7 controls NGN3 stability and pancreatic endocrine lineage development

USP7 controls NGN3 stability and pancreatic endocrine lineage development

A simple tool for the synchronous differentiation of human induced pluripotent stem cells into pancreatic progenitors

Potential Use of Organoids in Regenerative Medicine

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